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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Publikationen des W. G. Kerckhoff-Instituts     Display Documents

ID: 428388.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis
Authors:Korfei, M.; Ruppert, C.; Mahavadi, P.; Henneke, I.; Markart, P.; Koch, M.; Lang, G.; Fink, L.; Bohle, R. M.; Seeger, W.; Weaver, T. E.; Guenther, A.
Date of Publication (YYYY-MM-DD):2008
Title of Journal:Am J Respir Crit Care Med
Issue / Number:8
Start Page:838
End Page:846
Audience:Not Specified
Abstract / Description:RATIONALE: The molecular pathomechanisms underlying idiopathic pulmonary fibrosis (IPF) are elusive, but chronic epithelial injury has recently been suggested as key event. OBJECTIVES: We investigated the possible implication of endoplasmic reticulum (ER) stress-mediated apoptosis in sporadic IPF. METHODS: We analyzed peripheral explanted lung tissues from patients with sporadic IPF (n = 24), chronic obstructive pulmonary disease (COPD) (n = 9), and organ donors (n = 12) for expression of major ER stress mediators and apoptosis markers by means of immunoblotting, semiquantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and the TUNEL method. MEASUREMENTS AND MAIN RESULTS: Compared with COPD and donor lungs, protein levels of ER stress mediators, such as processed p50 activating transcription factor (ATF)-6 and ATF-4 and the apoptosis-inductor CHOP (C/EBP-homologous protein), as well as transcript levels of spliced X-box binding protein (XBP)-1, were significantly elevated in lung homogenates and type II alveolar epithelial cells (AECIIs) of IPF lungs. Proapoptotic, oligomeric forms of Bax, which play a key role in ER stress-mediated apoptosis downstream of CHOP induction, as well as caspase-3 cleavage, could be detected in IPF lungs. By means of immunohistochemistry, exclusive induction of active ATF-6, ATF-4, and CHOP in AECIIs was encountered in IPF but not in COPD or donor lungs. Immunoreactivity was most prominent in the epithelium near dense zones of fibrosis and fibroblast foci, where these ER stress markers colocalized with markers of apoptosis (TUNEL, cleaved caspase-3). CONCLUSIONS: Severe ER stress response in the AECIIs of patients with sporadic IPF may underlie the apoptosis of this cell type and development of fibrosis in this disease.
Free Keywords:Activating Transcription Factor 4/biosynthesis/genetics Activating Transcription Factor 6/biosynthesis/genetics Apoptosis/*physiology Blotting, Western DNA-Binding Proteins/biosynthesis/genetics Endoplasmic Reticulum/*metabolism/pathology Female Gene Expression Humans Immunohistochemistry In Situ Nick-End Labeling Male Middle Aged Oxidative Stress/*physiology Pulmonary Alveoli/metabolism/pathology Pulmonary Disease, Chronic Obstructive/genetics/metabolism/pathology Pulmonary Fibrosis/genetics/metabolism/*pathology RNA/genetics Reverse Transcriptase Polymerase Chain Reaction Severity of Illness Index Transcription Factors/biosynthesis/genetics
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
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